Tier- Wise Collection of PK Data That Would Better Define Dose Across… – Species – Life Stages – Route – Frequency and Duration of Exposure Objectives (Continued)

HESIHESI ILSI Health and Environmental Sciences Institute

AGRICULTURAL CHEMICAL SAFETY ASSESSMENT (ACSA)

ADME Task Force Hugh A. Barton, PhD

National Center for Computational Toxicology Office of Research and Development US Environmental Protection Agency Research Triangle Park, NC

November 16, 2005 Hazard Characterization and Dose-Response Framework Response Response

Mode of Action Toxicodynamics limited information default Pharmacokinetics/ Toxicity Pathway Tissue Dosimetry Toxicokinetics

Exposure Exposure

Qualitative Quantitative Organization and Analysis Analysis Dose-Response-Time High

Animal Testing Mid Dose Human Exposure Low

Time Purpose of ADME Studies

Dose-Response: Obtain information to help determine the relationship between the concentration of free compound in plasma and the toxicological response. Risk: Provide data that assists in the design and interpretation of toxicity studies and the determination of risk. Objectives

Develop guidance for the careful, tier- wise collection of PK data that would better define dose across… – species – life stages – route – frequency and duration of exposure Objectives (continued)

Provide recommendations that would help in… – Toxicology study design – Interpretation – Risk Assessment Working through the process… Tox Studies -Time Course “Basic” -Metabolites Tier I -Bioavailability -Saturation Route-Route -Recovery Animal to Human Risk? Worker Safety ADME

-Route “Advanced” “Custom” -Age Tier III Interpret Tier II -Species

Internal Species Mode of Dose Differences Action “Basic” Tier I

Oral Bioavailability (iv, oral) Metabolism and Elimination Dose-Dependent PK Repeated-Exposure PK Blood levels in toxicity studies Assisting in Dose Selection

Plasma Time-Course: Dietary Exposure Dose selection for

chronic studies would 80 be improved with a 70 60

bioavailability 50 1000 ppm

m 40 7000 ppm

a assessment. l 50 000 ppm

p 30

L 20

m This is an example of /

μ 10 saturation of oral 0 absorption at doses 1h 2h 3h 4h 5h 6h 7h Time >7000 ppm in diet: Working through the process…

Tox Studies -Time Course “Basic” -Metabolites Tier I -Bioavailability -Saturation Route-Route -Recovery Animal to Human Risk? Worker Safety ADME

-Route “Advanced” “Custom” -Age Tier III Interpret Tier II -Species

Internal Species Mode of Dose Differences Action …For Interpretation

Dose-Response Mode of Action Internal Dose “Custom” Tier II Studies

Non-rodent PK Tissue/fluid distribution (including fetus/milk) In vitro metabolism: rodents/humans Serum protein binding Biliary excretion/enterohepatic recirculation Example: Species Relevance

The dog is uniquely more sensitive to organic acids like 2,4-D. Renal clearance studies suggest that the dog has a low capacity to excrete organic acids. Allometric comparison of the pharmacokinetic parameters: volume distribution (Vd), renal

clearance (Cl) and plasma half-life (t1/2) were conducted across species (including human).

Conclusion: the dog is an outlier. 100 A. 100000 B. Calf Human 10 10000 Pig Human 1000 Calf Human 1 Dog Pig 100 Vd L Rat 0.1 Cl ml hr-1 10 Rat Dog Mice 0.01 Mice 1

0.001 0.1 0.01 0.1 1 10 100 0.01 0.1 1 10 100 Body Weight (kg) Body Weight (kg) 1000 C.

5 mg/kg Comparative 100 Species PK Dog 1 mg/kg Human 10 Pig

t1/2 hr Calf

1 Mice Rat

0.1 0.01 0.1 1 10 100 Body Weight (kg) Working through the process…

Tox Studies -Time Course “Basic” -Metabolites Tier I -Bioavailability -Saturation Route-Route -Recovery Animal to Human Risk? Worker Safety ADME

-Route “Advanced” “Custom” -Age Tier III Interpret Tier II -Species

Internal Species Mode of Dose Differences Action “Advanced” Tier III

Route-to-Route Extrapolation – Dermal »In vitro rat/human »In vivo rat – Inhalation Biomonitoring Human clinical PK Working through the process…

New Compound: Tox Studies -Time Course “Basic” -Metabolites Tier I -Bioavailability -Saturation Route-Route -Recovery Animal to Human Risk? Worker Safety ADME

-Route “Advanced” “Custom” -Age Tier III Interpret Tier II -Species

Internal Species Mode of Dose Differences Action Working through the process… Mature Compound: Tox Studies -Time Course “Basic” -Metabolites Tier I -Bioavailability -Saturation Route-Route -Recovery Animal to Human Risk? Worker Safety ADME

-Route “Advanced” “Custom” -Age Tier III Interpret Tier II -Species

Internal Species Mode of Dose Differences Action Example Tier III Study: Human dermal absorption

Dermal is a major exposure route. In vitro studies can provide an initial estimate of dermal absorption. In vivo studies with human volunteers can establish extent of dermal absorption. Direct application for assessing human health risk. Conclusions/Recommendations

To be useful, ADME studies need to:

• Help in the design of toxicity studies. • Help interpret results from toxicity studies. • Help assess risk. Conclusions/Recommendations (continued)

Generalized tiered approach

• Basic (Tier I), which would include data that are crucial for toxicity study design including dose selection, half-life determinations for recovery period determination, and the identification of major metabolites.

• Custom (Tier II), which would include data needed for study interpretation, absorbed dose estimates, and duration/route extrapolations.

• Advanced (Tier III), which would include data to support the understanding of a compound’s mode of action and allow the derivation of pharmacodynamic concordance. ADME Task Force Members Co-Chairs: Hugh Barton (USEPA) and Timothy Pastoor (Syngenta Crop Protection)

Karl Baetcke (US EPA) Bernhard Stahl (Bayer CropScience) Jan Chambers (MS State University) Chuck Timchalk (Pacific NW National Laboratory) Janet Diliberto (US EPA) Jeff Driver LIAISONS: (infoscientific.com) Alan Boobis (Imperial Chuck Hastings (BASF) College London) – Systemic Sesh Iyengar (Bayer Toxicity Task Force CropScience) Larry Sheets (Bayer Robert Krieger (University of Corporation) – Life Stages CA, Riverside) Task Force